This invention relates to the synthesis of, methods of using, and compositions comprising bupropion metabolites, their isomers, and salts thereof.
Bupropion, a racemic mixture of (+)- and (xe2x88x92)-1-(3-chlorophenyl)-2-[(1,1-dimethylethyl)amino]-1-propanone, is an antidepressant of the aminoketone class, which is described in U.S. Pat. Nos. 3,819,706 and 3,885,046. The hydrochloride salt of bupropion is sold under the tradenames WELLBUTRIN(copyright) and WELLBUTRIN SR(copyright) (Glaxo Wellcome Inc.) for the treatment of depression. Bupropion is also sold under the tradename ZYBAN(copyright) (Glaxo Wellcome Inc.) as a drug useful to achieve smoking cessation. Additional benefits of bupropion maleate are reported in European Patent Application No. 118036.
Although its mechanism of action is poorly understood, bupropion is reportedly a weak but selective inhibitor of dopamine. Its potency as an inhibitor of norepinephrine reuptake is reportedly only half of that for dopamine, and it shows little affinity for the serotonergic transport system. Ascher, J. A., et al., J Clin. Psychiatry, 56:395-401 (1995).
Bupropion is extensively metabolized in man and animal. Three metabolites found in the plasma of healthy humans to whom it has been administered are shown in Scheme 1: 
Posner, J., et al., Eur. J. Clin Pharmacal., 29:97-103 (1985); Suckow, R. F., et al., Biomedical Chromatography, 11:174-179 (1997). Referring to Scheme 1, metabolite 1 has the chemical name 2-(3-chlorophenyl)-2-hydroxy-3,5,5-trimethyl-morpholinol; metabolite 2 has the chemical name 2-(tert-butylamino)-1-(3-chlorophenyl)-propane-1-ol; and metabolite 3 has the chemical name 1-(3-chlorophenyl)-2-[(1,1-dimethylethanol)amino]-1-propanone. Because bupropion is administered as a racemate and its metabolites are chiral, stereomeric mixtures of each of the metabolites 1, 2, and 3 likely exist in human plasma following its administration.
The bupropion metabolite 1, often referred to as xe2x80x9chydroxybupropion,xe2x80x9d has two chiral carbon atoms and can thus theoretically exist as two pairs of enantiomers. These are shown in Scheme 2: 
Based on studies using racemic bupropion in mice, it has been suggested that racemic hydroxybupropion may contribute to the antidepressant profile of racemic bupropion in depressed patients. Kelley, J. L., et al., J. Med. Chem., 39:347-349 (1996). The mixture 1a has been isolated from human plasma and allegedly separated into its (S,S) and (R,R) components. Suckow, R. F., et al., Biomedical Chromatography, 11:174-179 (1997). However, activity of the individual enantiomers was not reported in Suckow.
The amino alcohol metabolite 2, also referred to as xe2x80x9cdihydrobupropion,xe2x80x9d can also exist as two pairs of enantiomers. These are shown in Scheme 3: 
The pair wherein the alcohol and amine moietics are cis to each other is commonly referred to as the erythro-amino alcohol metabolite; the pair wherein the two moieties are trans to each other is referred to as the threo-amino alcohol metabolite.
The tert-butyl alcohol metabolite 3 can exist as one of two enantiomers. This racemic metabolite, the accumulation of which in human plasma coincides with the elimination of a single dose of bupropion, is believed by some to be a precursor to hydroxybupropion. Posner, J., et al., Eur. J. Clin. Pharmacol., 29:97-103 (1985); Suckow, R. F., et al., Biomedical Chromatography, 11: 174-179 (1997).
Clearly, the metabolism of bupropion, which is complicated and poorly understood, results in a complex array of chiral compounds. The structures of these molecules and their chirality provide the skilled artisan with difficult issues of asymmetric synthesis, chiral resolution, and pharmacological activity.
Racemic bupropion is widely used to treat affective disorders in patients who do not respond to, or cannot tolerate, other antidepressants such as tricyclic agents or monoamine oxidase inhibitors. Examples of affective disorders are depression and bipolar manic-depression. Racemic bupropion is also useful in the treatment of other diseases or conditions associated with the reuptake of neuronal monoamines such as serotonin and norepinephrine. These reportedly include: schizophrenia (U.S. Pat. No. 5,447,948); attention-deficit disorder; psycho-sexual dysfunction (U.S. Pat. No. 4,507,323); bulimia and other eating disorders; Parkinson""s disease; migraine (U.S. Pat. No. 5,753,712); and chronic pain. Racemic bupropion also reportedly increases success rates in some smoking cessation treatments. Rose, J. E., Annu. Rev. Med., 47:493-507 (1996); Ferry, L. H. et al., J. Addict. Dis., 13:A9 (1994); and Lief, H. I., Am. J. Psychiatry, 153(3):442 (1996).
Further uses of racemic bupropion reportedly include the treatment of: the effects of ethanol (U.S. Pat. No. 4,393,078); tardive dyskinesia (U.S. Pat. No. 4,425,363); drowsiness (U.S. Pat. Nos. 4,571,395 and 4,798,826); minimal brain dysfunction (U.S. Pat. No. 4,435,449); psychosexual dysfunction (U.S. Pat. No. 4,507,323); prostate hypertrophy and sexual dysfunction (U.S. Pat. No. 4,835,147); psychostimulant addiction (U.S. Pat. No. 4,935,429); substance abuse (U.S. Pat. No. 5,217,987); high cholesterol (U.S. Pat. No. 4,438,138); and weight gain (U.S. Pat. No. 4,895,845).
Certain advantages exist in using bupropion for the treatment of diseases and conditions. For example, bupropion does not inhibit monoamine oxidase or block the reuptake of serotonin, unlike other neuronal monoamine reuptake inhibitors. Administration of bupropion can thus avoid or lessen many adverse effects commonly associated with other antidepressants such as tricyclic agents and monoamine oxidase inhibitors.
Unfortunately, racemic bupropion is not free of adverse effects. Administration of the drug can cause seizures, especially in patients currently taking the monoamine oxidase inhibitor phenelzine. Other frequently reported adverse effects associated with the use of racemic bupropion include nausea, vomiting, excitement, agitation, blurred or blurry vision, restlessness, postural tremors, hallucinations/confusional states with the potential for abuse, anxiety, insomnia, headaches and/or migraines, dry mouth, constipation, tremor, seizures, sleeping disturbances, dermatologic problems (e.g., rashes), neuropsychiatric signs and symptoms (e.g. delusions and paranoia), and weight loss or gain. See, e.g., Physicians"" Desk Reference(copyright) 1252-1258 (53rd ed. 1999). These effects are dose limiting in a number of patients, and can be particularly dangerous for Parkinson""s patients.
Thus, there remains a need for a drug that provides the advantages of racemic bupropion, but with fewer disadvantages. Compounds and pharmaceutical compositions are desired that can be used for the treatment and prevention of disorders and conditions while reducing or avoiding adverse effects associated with the administration of racemic bupropion.
This invention encompasses methods of making and using bupropion metabolites and pharmaceutically acceptable salts, solvates, hydrates, and clathrates thereof, and pharmaceutical compositions and dosage forms comprising bupropion metabolites and pharmaceutically acceptable salts, solvates, hydrates, and clathrates thereof. In particular, the invention provides methods of synthesizing optically pure (S,S)-hydroxybupropion, and optically pure (R,R)-hydroxybupropion. In addition, the invention encompasses methods of synthesizing optically pure (S,S)-dihydrobupropion, (R,R)-dihydrobupropion, (S,R)-dihydrobupropion, and (R,S)-dihydrobupropion.
The invention further provides methods of treating and preventing conditions that include, but are not limited to, sexual dysfunction, affective disorders, cerebral function disorders, substance addiction, tobacco smoking, and incontinence. Methods of the invention comprise administering to a patient in need of such treatment or prevention, a therapeutically or prophylactically effective amount of a bupropion metabolite, or a pharmaceutically acceptable salt, solvate, hydrate, or clathrate thereof. Additional methods of the invention further comprise the use of at least one additional physiologically active agent such as a selective serotonin reuptake inhibitor (xe2x80x9cSSRIxe2x80x9d), 5-HT3 antagonist, or nicotine with a bupropion metabolite of the invention.
Pharmaceutical compositions and dosage forms of the invention comprise a therapeutically or prophylactically effective amount of a bupropion metabolite or a pharmaceutically acceptable salt, solvate, hydrate, or clathrate thereof, and optionally at least one additional physiologically active agent such as a SSRI, 5-HT3 antagonist, or nicotine.
As used herein, the term xe2x80x9cpatientxe2x80x9d includes mammals, and preferably humans.
As used herein, the tern xe2x80x9cbupropion metabolitexe2x80x9d includes, but is not limited to, racemic and optically pure forms of 2-(3-chlorophenyl)-2-hydroxy-3,5,5-trimethyl-morpholinol (also known as hydroxybupropion), 2-(tert-butylamino)-1-(3-chlorophenyl)-propan-1-ol (also known as dihydrobupropion), and 1-(3-chlorophenyl)-2-[(1,1-dimethylethanol)amino]-1-propanone. As used herein, the term xe2x80x9coptically pure bupropion metabolitexe2x80x9d includes, but is not limited to, optically pure: (R,R)-2-(3-chlorophenyl)-2-hydroxy-3,5,5-trimethyl-morpholinol (also called (R,R)-hydroxybupropion); (S,S)-2-(3-chlorophenyl)-2-hydroxy-3,5,5-trimethyl-morpholinol (also called (S,S)-hydroxybupropion); (R,R)-2-(tert-butylamino)-1-(3-chlorophenyl)-propan-1-ol (also called (R,R)-dihydrobupropion); (S,R)-2-(tert-butylamino)-1-(3-chlorophenyl)-propan-1-ol (also called (S,R)-dihydrobupropion); (S,S)-2-(tert-butylamino)-1-(3-chlorophenyl)-propan-1-ol (also called (S,S)-dihydrobupropion); (R,S)-2-(tert-butylamino)-1-(3-chlorophenyl)-propan-1-ol (also called (R,S)-dihydrobupropion); (R)-1-(3-chlorophenyl)-2-[(1,1-dimethyl-ethanol)amino]-1-propanone; and (S)-1-(3-chlorophenyl)-2-[(1,1-dimethylethanol)amino]-1-propanone.
As used herein to describe a compound, the terms xe2x80x9csubstantially optically pure,xe2x80x9d xe2x80x9coptically pure,xe2x80x9d xe2x80x9coptically pure enantiomer,xe2x80x9d and xe2x80x9cstereomerically purexe2x80x9d mean that the compound contains greater than about 90% of the desired stereoisomer by weight, preferably greater than about 95% of the desired stereoisomer by weight, and most preferably greater than about 99% of the desired stereoisomer by weight, said weight percent based upon the total weight of the stereoisomer(s) of the compound. As used herein to describe a compound, the term xe2x80x9csubstantially freexe2x80x9d means that the compound contains less than about 10% by weight, preferably less than about 5% by weight, and more preferably less than about 1% by weight of the undesired stereoisomer(s).
As used herein, the term xe2x80x9cadjunctively administeredxe2x80x9d refers to the administration of one or more compounds in addition to a bupropion metabolite, either simultaneously with the bupropion metabolite or at intervals prior to, during, or following administration of the bupropion metabolite to achieve the desired therapeutic or prophylactic effect.
As used herein, the terms xe2x80x9cdiastereomersxe2x80x9d and xe2x80x9cdiastereomericxe2x80x9d refer to stereoisomers having distinct three-dimensional orientations that are not enantiomers. In particular these terms refer to compounds having two or more chiral centers.
As used herein, the term xe2x80x9cstereoisomersxe2x80x9d refers to compounds possessing at least one chiral center, i.e., compounds containing at least one carbon atom having four different groups attached thereto.
As used herein, the term xe2x80x9cpharmaceutically acceptable saltxe2x80x9d refers to a salt prepared from a pharmaceutically acceptable non-toxic inorganic or organic acid or base. The compounds of the invention that are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids. Acids that can be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds of the invention are those that form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, such as, but not limited to, hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, formate, acetate, propionate, succinate, camphorsulfonate, citrate, acid citrate, fumarate, gluconate, isothionate, lactate, malate, mucate, gentisate, isonicotinate, saccharate, tartrate, bitartrate, para-toluenesulfonate, glycolate, glucuronate, maleate, furoate, glutamate, ascorbate, benzoate, anthranilate, salicylate, phentylacetate, mandelate, embonate (pamoate), methanesulfonate, ethanesulfonate, pantothenate, benzenesulfonate, stearate, sulfanilate, alginate, p-toluenesulfonate, and galacturonate. Particularly preferred anions are hydrobromide, hydrochloride, phosphate, acid phosphate, maleate, sulfate, and acid phosphate. Most preferred anions are hydrochloride and maleate.
Compounds of the invention that are acidic in nature are capable of forming salts with various phannaceutically acceptable bases. The bases that can be used to prepare pharmaceutically acceptable base addition salts of such acidic compounds of the invention are those that form non-toxic base addition salts, i.e., salts containing pharmacologically acceptable cations such as, but not limited to, alkali metal or alkaline earth metal salts and the calcium, magnesium, sodium or potassium salts in particular. Suitable organic bases include, but are not limited to, N,N-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumaine (N-methylglucamine), lysine, and procaine.
As used herein, the terms xe2x80x9cavoiding adverse effectsxe2x80x9d and xe2x80x9cavoiding adverse effectsxe2x80x9d mean eliminating or reducing at least one adverse effect associated with the administration of a particular compound or mixture of compounds.
As used herein, the term xe2x80x9cadverse effects associated with racemic bupropionxe2x80x9d includes, but is not limited to, seizures, nausea, vomiting, excitement, agitation, blurred or blurry vision, restlessness, postural tremors, hallucinations/confusional states with the potential for abuse, anxiety, insomnia, headaches and/or migraines, dry mouth, constipation, tremors, sleeping disturbances, dermatologic problems (e.g., rashes), neuropsychiatric signs and symptoms (e.g., delusions and paranoia), and weight gain.
As used herein, the term xe2x80x9cadverse effects associated with the inhibition of dopamine reuptakexe2x80x9d includes, but is not limited to, seizures, nausea, vomiting, excitement, agitation, blurred or blurry vision, restlessness, postural tremors, hallucinations/confusional states with the potential for abuse, anxiety, insomnia, headaches and/or migraines, dry mouth, constipation, tremor, sleeping disturbances, dermatologic problems (e.g., rashes), neuropsychiatric signs and symptoms (e.g., delusions and paranoia), and weight gain.
As used herein, the terms xe2x80x9cdisorder ameliorated by the inhibition of neuronal monoamine reuptakexe2x80x9d and xe2x80x9cdisorder related to reuptake of neuronal monoaminesxe2x80x9d mean an acute or chronic disease, disorder, or condition having symptoms that are reduced or alleviated by the inhibition of neuronal monoamine reuptake, and especially by the inhibition of norepinephrine (or noradrenaline) and serotonin reuptake. Disorders ameliorated by inhibition of neuronal monoamine reuptake include, but are not limited to, erectile dysfunction, affective disorders, cerebral function disorders, tobacco smoking, and incontinence.
As used herein, the term xe2x80x9caffective disorderxe2x80x9d includes, but is not limited to, depression, anxiety disorders, attention deficit disorder, attention deficit disorder with hyperactivity, bipolar and manic conditions, bulimia, obesity or weight-gain, narcolepsy, chronic fatigue syndrome, seasonal affective disorder, premenstrual syndrome, substance addiction or abuse, and nicotine addiction.
As used herein, the term xe2x80x9csubstance addictionxe2x80x9d includes, but is not limited to, addiction to cocaine, heroin, nicotine, alcohol, opioids, anxiolytic and hypnotic drugs, cannabis (marijuana), amphetamines, hallucinogens, phencyclidine, volatile solvents, and volatile nitrites. Nicotine addiction includes nicotine addiction of all known forms, such as smoking cigarettes, cigars and/or pipes, and addiction to chewing tobacco.
As used herein, the terms xe2x80x9cattention deficit disorderxe2x80x9d (ADD), xe2x80x9cattention deficit disorder with hyperactivityxe2x80x9d (ADDH), and xe2x80x9cattention deficit/hyperactivity disorderxe2x80x9d (AD/HD), are used in accordance with their accepted meanings in the art. See, e.g., Diagniostic and Statistical Manual of Mental Disorders, Fourth Ed., American Psychiatric Association, 1997 (DSM-IV(trademark)) and Diagnostic and Statistical Manual of Mental Disorders, 3rd Ed., American Psychiatric Association (1981) (DSM-III(trademark)).
As used herein, the term xe2x80x9cdepressionxe2x80x9d includes a disease or condition characterized by changes in mood, feelings of intense sadness, despair, mental slowing, loss of concentration, pessimistic worry, agitation, and self-deprecation. Physical symptoms of depression that may be reduced or alleviated by the methods of the invention include insomnia, anorexia, weight loss, decreased energy and libido, and abnonnal hormonal circadian rhythms.
As used herein, the term xe2x80x9ccerebral function disorderxe2x80x9d includes, but is not limited to, disorders involving intellectual deficits such as senile dementia, Alzheimer""s type dementia, memory loss, amnesia/amnestic syndrome, epilepsy, disturbances of consciousness, coma, lowering of attention, speech disorders, Parkinson""s disease, Lennox syndrome, autistic disorder, autism, hyperkinetic syndrome and schizophrenia. Also within the meaning of the term are disorders caused by cerebrovascular diseases including, but not limited to, cerebral infarction, cerebral bleeding, cerebral arteriosclerosis, cerebral venous thrombosis, head injuries, and the like where symptoms include disturbance of consciousness, senile dementia, coma, lowering of attention, and speech disorders.
As used herein, the term xe2x80x9cmethod of treating Parkinson""s diseasexe2x80x9d means relief from the symptoms of Parkinson""s disease which include, but are not limited to, slowly increasing disability in purposeful movement, tremors, bradykinesia, rigidity, and a disturbance of posture.
As used herein, the tern xe2x80x9csexual dysfunctionxe2x80x9d encompasses sexual dysfunction in men and women caused by psychological and/or physiological factors. Examples of sexual dysfunction include, but are not limited to, erectile dysfunction, premature ejaculation, vaginal dryness, vaginismus, decreased libido, lack of sexual excitement, anorgasmia, or inability to obtain orgasm. The term xe2x80x9csexual dysfunctionxe2x80x9d further encompasses psycho-sexual dysfunction. Examples of psycho-sexual dysfunction include, but are not limited to, inhibited sexual desire, inhibited sexual excitement, inhibited female orgasm, inhibited male orgasm, premature ejaculation, functional dyspareunia, functional vaginismus, and atypical psychosexual dysfunction.
As used herein, the term xe2x80x9cmethod of treating or preventing sexual dysfunctionxe2x80x9d means prevention of, or relief from, sexual dysfunction or one or more symptoms of sexual dysfunction.
As used herein, the term xe2x80x9cmethod of treating or preventing psycho-sexual dysfunctionxe2x80x9d means prevention of, or relief from, a symptom of inhibited sexual desire, inhibited sexual excitement, inhibited female orgasm, inhibited male orgasm, premature ejaculation, functional dyspareunia, functional vaginismus, and atypical psychosexual dysfunction.
As used herein, the term xe2x80x9ca method for treating obesity or weight gainxe2x80x9d means reduction of weight, relief from being overweight, relief from gaining weight, or relief from obesity, all of which are usually due to extensive consumption of food.
As used herein, the term xe2x80x9ca method of treating or preventing incontinencexe2x80x9d means prevention of or relief from the symptoms of incontinence including involuntary voiding of feces or urine, and dribbling or leakage of feces or urine which may be due to one or more causes including, but not limited to, pathology altering sphincter control, loss of cognitive function, overdistention of the bladder, hyper-reflexia and/or involuntary urethral relaxation, weakness of the muscles associated with the bladder, or neurologic abnormalities. As used herein, the term xe2x80x9curinary incontinencexe2x80x9d encompasses stress urinary incontinence and urge urinary incontinence.